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Molecules ‘too dangerous for nature’ kill cancer cells

By Andy Coghlan

THAT which nature abhors could help combat cancer, say researchers who’ve developed and tested weird compounds called nullomers. Their name comes from the Latin word “nullus” for nothing, and the fact that although they can theoretically exist naturally, they don’t, possibly because they’re too toxic or useless to life, and so the DNA sequences that encode them have been evolved out of existence.

Now, two nullomers have been shown to kill cells of two common types of cancer – breast and prostate – as well as a form of leukaemia. Yet they seem to spare healthy cells, which rapidly become immune to any ill effects. “To our surprise, the normal cells adapt and become less sensitive to the nullomers, whereas the effects on cancer cells increase with time,” says Greg Hampikian of Boise State University in Boise, Idaho, and head of the team developing and testing the nullomers. He thinks they might work by depleting energy production in cancerous but not healthy cells, but his investigations into how they kill cells are ongoing.

Hampikian made nullomers after analysing all publicly available genomes of living things, then working out which DNA sequences coding for peptides five amino acids long were absent from nature’s inventory. He discovered that of 3.2 million combinations possible for such peptides, 198 were absent. Then, he set about making those peptides.

After screening them, he identified two, codenamed 9R and 9S1, that were particularly effective against cancer cells. The results, published in Peptides (DOI&colon; 10.1016/j.peptides.2012.09.015), show that within two days, cancer cells became more sensitive to the nullomers, whereas healthy cells became more resistant.

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Even more potent

The concentrations required to kill half a population of prostate or breast cancer cells dropped within 48 hours to as little as a third of the original level, whereas healthy skin and blood cells grew tolerant to the nullomers.

Further investigations showed that the nullomers killed the cancer cells by disrupting energy production in mitochondria, the powerhouses of cells, their output of the energy molecule ATP dropping practically to zero. Hampikian is now investigating this in more detail to find out why nullomers damage cancerous cells but spare healthy ones. “There are so many basic differences between cancer and normal cells, everything from how fast they reproduce to how they metabolise sugar, so we’re working on some of those variables now,” he says.

Hampikian and his colleagues are altering nullomers chemically to try to make them even more effective. “We expect a big increase in potency,” he says. However, he doubts they could combat cancer alone, and envisions use in combination with other drugs to reduce the chance that cancer cells will develop resistance to them.

The work gets a cautious welcome from Ali Tavassoli, a cancer researcher at the University of Southampton&colon; “These findings are promising, but it’s important to stress that they’ve only been tested on cells in the lab. Further studies of how these peptides might behave in humans, especially their stability and resistance to degradation, are needed before we know if they could be suitable drug candidates.”